A variety of clinical methods exist by which a physician is directed to a diagnosis of the cause of apparent seizures in a patient as either epilepsy or otherwise. For example, routine blood studies including electrolyte and glucose measurements, complete blood counts, and toxin screens may be carried out to assist a physician in determining a cause of seizures in a patient. Medical imaging, including CT and MRI, as well as EEG examinations may also yield valuable clinical information in this regard. There are, however, no routinely used prospective or predictive clinical tests which a physician may perform which indicate whether or not a patient is at risk of developing seizures in the future.
Retrospective studies have revealed that several factors are associated with an increased risk of seizure, for example, a familial history of seizures, meningitis, or a recent head trauma. An individual's susceptibility to seizure is determined additionally by the individual's brain chemistry, and consequently a head trauma of equal magnitude, e.g., may precipitate seizures in one individual, but not another. Presently, there is no predictive test to distinguish between these two hypothetical individuals.
To the contrary, following head trauma or insult to the brain it is common practice to administer prophylactically anti-seizure drugs to most patients who fall into an “at risk” category, without any analysis of the individual's actual risk. Accordingly, patients who are at lower risk of developing seizures are subjected to the unnecessary side-effects of various drugs, such as, e.g., inhibition of neuroplasticity. A need remains, therefore, for a predictive test which more accurately indicates a patient's actual risk of developing seizures.
Distinguishing pseudoseizures from seizures is another clinical need that such a test may address. Pseudoseizures are seizure-like spells with no physiological basis. They can either be intentionally or subconsciously induced. The treatment for pseudoseizures is often psychological in nature, and patients undergo unnecessary effects if anticonvulsant medication is administered due to a misdiagnosis.
Although epileptic seizures are rarely fatal, large numbers of patients require medication to avoid the disruptive, and potentially dangerous, consequences of seizures. In many cases, medication is required for extended periods of time, and in some cases, a patient must continue to take prescription drugs for life. Furthermore, drugs used for the management of epilepsy have side-effects associated with prolonged usage, and the cost of the drugs can be considerable.
It has been postulated that free amino acids play a role in the normal functioning of the central nervous system. Amino acid concentrations in the brain specifically depend on several factors, including tissue metabolism, blood flow, transport or exclusion at the blood brain barrier, and renal or hepatic function. As such, amino acid imbalances associated with neurological disorders are of interest and have served as the basis for a variety of investigations.
However, the findings of previous studies on amino acid imbalances in epilepsy, including those by Plum (Journal of Neurochemistry 1974, 23, 595–600), Mutani et al. (Epilepsia 1974, 15, 595–597), Crawford and Chadwick (Epilepsy Research 1987, 1, 328–338), Haines et al. (Epilepsia 1985, 26, 642–648), Monaco et al. (Italian Journal of Neurological Sciences 1994, 15, 137–14), van Gelder et al. (Neurochemical Research 1980, 5, 659–671), and Ferrie et al. (Epilepsy Research 1999, 34, 221–229), are inconsistent. In addition to methodological sources of variation, inter-study variability has been attributed to such factors as heterogeneity within the sample population being examined, circadian variation and short-term dietary amino acid intake.
Anti-epileptic medication may also contribute to inter-study variability as increases in glycine, serine and alanine, have been noted upon valproic acid administration, while increases in free and total β-aminobutyric acid, homocarosine (a conjugate of β-aminobutyric acid), β-alanine, glycine and β-aminoisobutyric acid occur upon vigabatrin administration. Alternatively, administration of carbamazepine, ethosuximide and mephobarbital leads to decreases in leucine, proline and phenylalanine, respectively.